This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We are currently testing the therapeutic potential of a DNA/MVA SIV vaccine in macaques infected with SIV239 or 251 in combination with anti-retroviral therapy (ART). This DNA/MVA SIV vaccine is a prototype of HIV vaccine that is currently being tested in healthy human volunteers for immunogenicity (Phase 2a) in US through HVTN/Geovax Inc. Two pilot studies, TH-12 and TH-32, have been completed. TH-12 tested whether therapeutic vaccination had the potential to be effective in macaques placed on ART soon after infection (12 weeks);and TH-32 tested for therapeutic potential late after infection when the group is developing AIDS (32 weeks). TH-18 is currently testing an intermediate time, 18 weeks post infection. SIV infections are a good model for therapeutic HIV vaccines because over the course of pathogenic simian immunodeficiency virus infections there is a progressive loss of viral control due to the destruction of CD4 T cells, CD8 T cell exhaustion, and the selection of viral mutations that allow CD8 T cell and neutralizing antibody (Ab) escape. The results of the pilot studies suggest the following important findings: (1) Vaccinations combined with ART elicit highly functional CD8 and CD4 T cells irrespective of either early (12-18 weeks) or late (32 weeks) ART initiation. (2) However, vaccinations combined with early ART (prior to substantial viral escape and immune system destruction) are more effective than vaccinations combined with late ART. (3) The breadth of the elicited CD8 T cell epitopes for Gag and their match to the CD8 T cell response stimulated by the re-emergent virus is important for control.